Oxidation of 2, 5-dialkyl pyridines



United States Patent '0 OXIDATION OF 2,5-DIALKYL PYRIDINES Milton E. Abraham, Cresskill, N.J., and Godfrey Wilbert,

Carmel, N.Y., assignors, by mesne assignments, to Warher-Lambert Pharmaceutical Company, Morris Plains, NJ., a corporation of Delaware No Drawing. Application December 1, 1955 Serial No. 550,486

4 Claims. (Cl. 260-2955) This invention relates to the oxidation of 2,5'-dialkyl pyridine compounds and relates more particularly to an improved catalytic process for the nitric acid oxidation of Z-methyl-S-ethyl pyridine.

Pyridine carboxylic acids such as niacin and isocin chomeronic acid have been obtained by the controlled oxidation of alkyl pyridine compounds. The alkyl pyridines which have been utilized in this oxidation process include the picolines and lutidines. Pyridine compounds containing longer-chain alkyl substituents have also been found satisfactory for use in this process, particularly 2-methyl-5-ethyl pyridine. The catalytic nitric acid oxidation of Z-methyl-S-ethyl pyridine has been suggested, and the reaction conditions recommended for carrying out this particular process have included the use of aqueous nitric acid of from 5 to 40% concentration and temperatures upv to about 220 C. Others who have been con- 'ice 2,5-dialkyl pyridine with nitric acid, if the oxidation is carried out at a temperature of at least 250 C. and under a pressure of at least 750 pounds per square inch gauge, employing a soluble salt of iron as catalyst. The use of catalytic amounts of iron and of high pressure, in conjunction with temperatures higher than heretofore employed when carrying out said oxidation reaction, has been found to give yields of niacin and isocinchomeronic acid of as high as 98% of theory, which is considerably higher than has been previously obtained.

In carrying out our novel oxidation process, we may employ any 2,5-dialkyl pyridine such as 2,5-dimethyl pyridine or 2-methyl-5-ethyl pyridine, for example. The latter is preferred since it is readily available from synthetic procedures and in any desired quantities.

The nitric acid concentration we employ for carrying out said catalytic oxidation may be from 5 to 40% by tion of the 2,5-dialkyl pyridine already in the reaction cerned with this reaction have proposed the use of nitric acid of a concentration of 40 to 95% and temperatures of up to 200 C., the reaction being carried out under pressures as high as 700 p.s.i.g. While the yields obtained under these conditions are appreciable they have not been higher than about 70% of theoretical. Higher yields have been obtained by relying upon the use of substantial, at least stoichiometric, amounts of copper during the oxidation reaction so that the copper salts of the carboxylic acids formed are obtained and are thus separated from the reaction. Although high yields are obtainable, the latter expedient is quite cumbersome, process-wise, since it entails breaking up the copper salt before the free acids may be obtained.

Another disadvantageous factor in the processes 'here tofore employed for the oxidation of 2,5-dialkyl pyridines is that the reaction mixture obtained after the completion of the oxidation reaction consists of a relatively concentrated nitric acid solution usually containing at least 10% by weight of nitric acid. Since niacin is quite soluble in nitric acid of this concentration the separation of this product firstrequired neutralization of the unreacted nitric acid with an alkaline agent. Under these conditions not only was the cost increased because of the necessity for using a neutralizing agent but the nitrate salts thus formed further complicated the separation of the niacin. I

It is, therefore, an important object of this invention to provide an improved process for the nitric acid oxidation of a 2,5-dialkyl pyridine whereby niacin and isocinchomeronic acid are obtained in greatly improved yield.

Another object of this invention is the provision of an improved, continuous process for the catalytic, nitric acid oxidation of 2,5-dialkyl pyridines to form niacin and isocinchomeronic acid wherein said reaction prodnets are more readily separated from the reaction mixture without excessive loss or consumption of nitric acid.

Other objects of this invention will appear from the following detailed description.

We have now found that improved yields of niacin and isocinchorneronic acid are obtained when oxidizing a zone. The iron catalyst may be present in an amount of from 0.01 to 0.2 mol for each mol of 2,5-dialkyl pyridine in the reaction mixture and is preferably employed in a ratio of 0.05 mol for each mol of the 2,5-dia1kyl pyridine.

While the reaction temperature should be at least 230 C., temperatures as high as 350 C. may also be satisfactorily employed.

The pressure maintained in the reaction zone should be at least 750 pounds per square inch gauge and may be as high as 2500 pounds per square inch gauge. Usually, pressures of about 800 to 900 pounds per square mm are satisfactory.

Ordinarily, the reactants are maintained under these reaction conditions for from 25 to 600 seconds to effect the desired oxidation before being cooled below reaction temperature to prevent excessive oxidation.

Preferably, at least partial cooling is eifected by flashing the reaction mixture so that the pressure is reduced rapidly from that maintained during the oxidation reaction to atmospheric or substantially atmospheric pressure, that is to from 0 to 150 p.s.i.g. Cooling the reaction mixture in this way is quite effective and is highly advantangeous in making the separation of the oxidation products simpler and more economical. By flashing the reaction mixture, substantially all of the nitric oxide is separated as a vapor. The substantial reduction in the concentration of the nitric acid, to no more than 1% by weight, makes the niacin and isocinchomeronic acid.

' formed far easier to separate since they are less soluble An aqueous reaction mixture consisting of 10 parts by weight of Z-methyl-S-ethyl pyridine, 31 parts by weight of nitric acid, 0.075 part by weight of iron (as ferric nitrate) and 59 parts by weight of water are passed into a reactor at a pressure of 820 pounds per square inch gauge, and while under this pressure the mixture is heated to a temperature of 256 C. The rate of flow through the reactor is adjusted so that the mixture is maintained at this temperature and pressure for about 130 seconds. After the desired oxidation of the Z-methyl-S-ethyl pyridine to niacin and isocinchomeronic acid has taken place the mixture is discharged to atmospheric pressure and the nitric oxide flashes off to a recovery system. The conversion of 2-methylS-ethyl pyridine to niacin and isocinchomeronic acid is 76.8% and an unreacted 21.2% is recovered.

Example II An aqueous reaction mixture consisting of parts by weight of 2-methyl-5-ethyl pyridine, 31 parts by weight of nitric acid, 0.075 part by weight of iron (as ferric nitrate) and 59 parts by weight of water are passed into a reactor at a pressure of 900 p.s.i.g., and While under this pressure is heated to a temperature of 256 C. The rate of flow through the reactor is adjusted so that the mixture is maintained at this temperature and pressure for about 320 seconds. After the desired oxidation of the Z-methyl-S-ethyl pyridine to niacin and isocinchomeronic acid has taken place, the mixture is discharged to atmospheric pressure and the nitric oxide present flashes off to a recovery system. The conversion of Z-methyl-S-ethyl pyridine to niacin and isocinchomeronic acid is 86%. 9.9% of the 2-methyl-5-ethyl pyridine is recovered.

Example III -An aqueous reaction mixture consisting of 10 parts by weight of Z-methyl-S-ethyl pyridine, 31 parts by weight of nitric acid, 0.075 part by weight of iron (as ferric nitrate) and 59 parts by weight of water are passed into a reactor at a pressure of 1250 p.s.i.g., and while under this pressure is heated to a temperature of 266 C. The rate of flow through the reactor is adjusted so that the mixture is maintained at this temperature and pressure for about 550 seconds. After the desired oxidation of the Z-methyl-S-ethyl pyridine to niacin and isocinchomeronic acid has taken place the mixture is discharged to atmospheric pressure and the nitric oxide flashes off to a recovery system. The conversion of 2-methyl-5-ethyl pyridine to niacin and isocinchomeronic acid is 77.2%. 12.4% of the Z-methyI-S-ethyl pyridine is recovered.

Example IV An aqueous reaction mixture consisting of 10 parts by weight of Z-methyl-S-ethyl pyridine, 31 parts by weight of nitric acid, 0.075 part by weight'of iron (as ferric nitrate) and 59 parts by weight of water are passed into a reactor at a pressure of 1200 p.s.i.g., and while under this pressure is heated to a temperature of 270 C. The rate of flow through the reactor is adjusted so that the mixture is maintained at this temperature and pressure for 400- 500 seconds. After the desired oxidation of the Z-methyl- S-ethyl pyridine to niacin and isocinchomeronic acid has taken place the mixture is discharged to atmospheric pressure and the nitric oxide flashes off to a recovery system. About 8.84% of the Z-methyI-S-ethyl pyridine is unreacted and is recovered. The nitric oxide flashed oif reduces the nitric acid content of the reaction medium to less than 1% It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of our invention.

. Having described our invention, what we desire to secure by Letters Patent is:

1. In a process for the oxidation of a 2,5-di-lower alkyl pyridine to niacin and isocinchomeronic acid, the steps which comprise forming a reaction mixture containing from 1 to 15% by weight of said dialkyl pyridine, at least 5.5 mols of aqueous nitric acid of a concentration of 5 to by weight for each mol of 2,5-dialkyl pyridine, and from 0.01 to 0.2 mol of iron, as a nitric acid soluble iron compound, passing the mixture through a reaction zone while at a temperature of at least 250 C. and under a pressure of at least 750 p.s.i.g., removing the resulting reaction mixture from the reaction zone, cooling the mixture by reducing the pressure to atmospheric, flashing nitric oxide ofl? and reducing the nitric acid in said reaction mixture to not more than about 1% by weight, and separating niacin and isocinchomeronic acid therefrom.

2. In a process for the oxidation of a 2,5-di-lower alkyl pyridine to niacin and isocinchomeronic acid, the steps which comprise forming a reaction mixture containing from 1 to 15% by weight' of said dialkyl pyridine, at least 5.5 mols of'aqueous nitric acid of a concentration of 5 to 40% by weight for each mol of 2,5-dialkyl pyridine, and from 0.01 to 0.2 mol of iron, as iron nitrate, passing the mixture through a reaction zone while at a temperature of at least 250 C. and under a pressure of at least 750 p.s.i.g., removing the resulting reaction mixture from the reaction zone, cooling the mixture by reducing the pressure to atmospheric, flashing nitric oxide oif and reducing the nitric acid in said reaction mixture to not more than about 1% by weight, and separating niacin and isocinchomeronic acid therefrom.

3. In a process for the oxidation of Z-methyl-S-ethyl pyridine to niacin and isocinchomeronic acid, the steps which comprise forming a reaction mixture containing from 1 to 15 by weight of said 2-rnethyl-5-ethyl pyridine, at least 5.5 mols of aqueous nitric acid of a concentration of 5 to 40% by weight for each mol of 2- methyl-S-ethyl pyridine, and from 0.01 to 0.2 mol of iron, as a nitric acid soluble iron compound, passing the mixture through a reaction zone while at a temperature of at least 250 C. and under a pressure of at least 750 p.s.i.g., removing the resulting reaction mixture from the reaction zone, cooling the mixture by reducing the pressure to atmospheric, flashing nitric oxide off and reducing the nitric acid in said reaction mixture to not more than about 1% by weight, and separating niacin and isocinchomeronic acid therefrom.

4. In a process for the oxidation of 2-methyl-5-ethyl.

pyridine to niacin and isocinchomeronic acid, the steps flashing nitric oxide oif and reducing the nitric acid insaid reaction mixture to not more'than about 1% by weight, and separating niacin and isocinchomeronic acid therefrom.

References Cited in the file of this patent UNITED STATES PATENTS Herring Oct. 27, 1953 OTHER. REFERENCES Sabatier: Catalysis in Org. Chem., p. 269, N.Y., Van Nostrand Co. (1923). 

1. IN A PROCESS FOR THE OXIDATION OF A 2,5-DI-LOWER ALKYL PYRIDINE TO NIACIN AND ISOCINCHOMERONIC ACID, THE STEPS WHICH COMPRISE FORMING A REACTION MIXTURE CONTAINING FROM 1 TO 15% BY WEIGHT OF SAID DIALKYL PYRIDINE, AT LEAST 5.5 MOLS OF AQUEOUS NITRIC ACID OF A CONCENTRATION OF 5 TO 40% BY WEIGHT FOR EACH MOL OF 2.5-DIALKYL PYRIDINE, AND FROM 0.01 TO 0.2 MOL OF IRON, AS A NITRIC ACID SOLUBLE IRON COMPOUND, PASSING THE MIXTURE THROUGH A REACTION ZONE WHILE AT A TEMPERATURE OF AT LEAST 250* C. AND UNDER A PRESSURE OF AT LEAST 750 P.S.I.G., REMOVING THE RESULTING REACTION MIXTURE FROM THE REACTION ZONE, COOLING THE MIXTURE BY REDUCING THE PRESSURE TO ATMOSPHERIC, FLASHING NITRIC OXIDE OFF AND REDUCING THE NITRIC ACID IN SAID REACTION MIXTURE TO NOT MORE THAN ABOUT 1% BY WEIGHT, AND SEPARATING NIACIN AND ISOCINCHOMERONIC ACID THEREFROM. 